Some drugs are potent inhibitors of hepatic microsomal enzymes, while others are inducers. In order to study the potent inhibitory/inducing effects of specific drugs on microsomal enzymes, we generally use marker probes which may be drug metabolites.
What kind of marker probe substrate to use if there are no metabolites of certain drugs (i.e., metformin is not metabolized) but if someone still wants to study its effects?
Sidhartha,
If I understood your question right one can evaluate the effect of in vivo administration of metformin (MET) on the activity of a constitutive cytochrome P450 dependent (microsomal mixed-function oxidase) enzyme. MET can inhibit cytochrome P450 aromatase.
Environmental xenobiotic compounds or endogenous ligands induce microsomal cytochrome P450 (CYP) 1A1 and CYP1B1 via the activation of the aryl hydrocarbon receptor (AhR). The inability of MET to bind to AhR (cytochrome P4501A1 (CYP1A1)/aryl hydrocarbon receptor) has been reported, suggesting that MET is not an AhR ligand. MET may inhibit the expression of CYP1A1 through an AhR ligand-independent mechanism. MET may impair CYP1A1 activity, which has been implicated in chemoprevention.
Dear Sidhartha,
The best approach is to characterize inhibitory effect of metformin on enzyme-kinetic parameters of metabolism of a well known CYP substrate. As itraconazole and metformin are often administered together to diabetic patients and have been shown to be metabolized via the same hepatic CYP3A subfamily in rats, in vivo inhibitory effects of metformin on Itraconazole might be assessed. Thus Dr. Choi and colleagues (Br J Pharmacol. 2010; 161: 815–829) have used of HPLC and pharmacokinetic analyses, to determine hepatic (after both i.v. and p.o. administration) and intestinal (after p.o. administration) concentrations of itraconazole and metformin after i.v. and p.o. administration of both drugs together. The significantly greater AUCs of itraconazole and metformin after i.v. administration of both drugs are probably due to competitive inhibition of the metabolism of each drug by each other via hepatic CYP3A1/2. Whereas after oral administration of both drugs, the significantly greater AUCs of each drug administered together than that of either drug alone is mainly due to competitive inhibition of intestinal metabolism of each drug by each other via intestinal CYP3A1/2.
Best wishes,
Ilya
Hi, Usually some people use ketoconazole do the studies, you can easily check google and get a right paper to start with.
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